During adolescent development decision-making and cognitive processes change in part due to changes to the structure, connectivity, and function of the prefrontal cortex (PFC). Most notably, the adolescent PFC undergoes significant stabilization of dendritic spine dynamics and reorganization of inhibitory connectivity. However, because puberty and adolescence co-occur, it has been difficult to causally determine if these changes to cognition, PFC structure, and function are puberty-dependent or independent. In 1967, the neurologist Lenneberg wrote that puberty marked the end of a period when the brain was more likely to recover from injury, neglect or disease. Today the onset of puberty is occurring earlier and earlier in western society (Aksglaede et al., 2009) yet it is not yet clear i this secular trend has negative consequences for brain and behavioral development in the PFC and other brain regions. Early puberty onset is associated with low socio-economic status (Lee et al., 2001) and a host of negative psychosocial and psychological outcomes including mental illnesses that are associated with dendritic remodeling and inhibition in the PFC (Ge et al., 2001, Weinberger, 1987). In order to determine if pubertal hormones reduce the structural dynamics of the PFC, I will advance or delay the age of puberty onset in female mice. I will use 2-photon in vivo imaging methods to follow the dynamic daily turnover of dendritic spines (Aim 1) and inhibitory axonal boutons (Aim 2) in the dorsomedial prefrontal cortex. Preliminary data collected in the sponsor lab show robust changes in these systems in the dmPFC of mice over the time-course of puberty onset, and support the hypothesis that gonadal hormones can rapidly alter the neurobiology and cognitive functions associated with this brain region. These data will contribute to establishing the specific mechanisms by which age at puberty onset does (or does not) affect the development of the PFC. These experiments will also help establish a model system by which to investigate the connections between synaptic remodeling and maturation of inhibition. It is anticipated that our highly controlled, sensitive, and cell-type specific experimental data from mice will help the larger health community determine how and why the current secular trend in puberty onset may (or may not) pose a threat to human health, development, and potential.